CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision

Abstract

During thymic development, T cell progenitors undergo positive selection based on the ability of their T cell Ag receptors (TCR) to bind MHC ligands on thymic epithelial cells. Positive selection determines T cell fate, in that thymocytes whose TCR bind MHC class I (MHC-I) develop as CD8-lineage T cells, whereas those that bind MHC class II (MHC-II) develop as CD4 T cells. Positive selection also induces migration from the cortex to the medulla driven by the chemokine receptor CCR7. In this study, we show that CCR7 is up-regulated in a larger proportion of CD4+CD8+ thymocytes undergoing positive selection on MHC-I compared with MHC-II. Mice bearing a mutation of Th-POK, a key CD4/CD8-lineage regulator, display increased expression of CCR7 among MHC-II-specific CD4+CD8+ thymocytes. In addition, overexpression of CCR7 results in increased development of CD8 T cells bearing MHC-II-specific TCR. These findings suggest that the timing of CCR7 expression relative to coreceptor down-regulation is regulated by lineage commitment signals.

Distinct phases in the positive selection of CD8+T cells distinguished by intrathymic migration and T-cell receptor signaling patterns

“…This analysis revealed a substantial population of CXCR4 lo CCR7 + DP thymocytes (Fig. 2E), consistent with a previous report (17). A detectable, although reduced, CXCR4 lo CCR7 + DP thymocyte population is also present among wild-type DP thymocytes (Fig.…”

“…Mature SP thymocytes remain in the thymus for 4-5 d (33) and thus may accumulate to outnumber the MHC class I-selected DP thymocytes in the steady-state thymus. Moreover, analysis of steady-state MHC class II-restricted thymocytes suggests that the switch in chemokine-receptor expression occurs during the early CD4 SP stage rather than at the DP stage (15)(16)(17). Therefore, it seems likely that steady-state medullary thymocytes consist primarily of CD4 and CD8 SP thymocytes, along with DP thymocytes bearing class I MHC-restricted TCR.…”

“…The switch in expression of CCR7 and CXCR4 can be detected on a substantial proportion of MHC class I-selected, but not MHC class II-selected DP thymocytes (15)(16)(17). Therefore, the timing of the switch in chemokine responsiveness and migration to the medulla appears to differ during CD4 versus CD8 T-cell development.…”

“…Conversely, mature SP thymocytes express CCR7 and have diminished expression of CXCR4 (12)(13)(14). For MHC class IIrestricted selection, chemokine-receptor changes appear to occur early during the SP stage whereas thymocytes undergoing positive selection via MHC class I up-regulate CCR7 at the DP stage (15)(16)(17). However, it is unclear whether the switch in chemokinereceptor expression and migration to the medulla occurs after positive selection is complete, or whether positive selection continues after thymocytes migrate to the medulla.…”

Dynamic control of β1 integrin adhesion by the plexinD1-sema3E axis

“…Double-negative (DN) thymocytes lacking expression of CD4 and CD8 as well as plexinD1 differentiate in the thymic cortex into largely nondividing CD4 + CD8 + double-positive (DP) thymocytes that display surface αβ T-cell receptors (TCRs) and express plexinD1 (6). Despite being highly mobile (7), DP thymocytes remain sequestered in the cortex in frequent physical association with thymic epithelial cells (TECs), moving toward the thymic medulla via chemokine guidance only subsequent to TCR stimulation by self-derived peptide/MHC complexes (pMHC) that induce CD69 expression and support cell survival, i.e., positive selection (8,9). CD69 + DP cells differentiate further into CD4 + CD8 − or CD4 − CD8 + singlepositive (SP) thymocytes, translocating to the thymic medulla to complete their maturation (10,11).…”